Two-step continuous-flow synthesis of 6-membered cyclic iodonium salts via anodic oxidation

We describe a multi-step continuous-flow procedure for the generation of six-membered diaryliodonium salts. The accompanying scalability and atom economy are significant improvements to existing batch methods. Benzyl acetates are submitted to this two-step procedure as highly available and cheap starting materials. An acid-catalyzed Friedel–Crafts alkylation followed by an anodic oxidative cyclization yielded a defined set of cyclic iodonium salts in a highly substrate-dependent yield.


General Information
Unless otherwise noted, all reactions were carried out under air. Reactions with chemicals sensitive to moisture or oxygen were carried out under a nitrogen atmosphere using standard Schlenk techniques. All chemicals were purchased from commercial suppliers and either used as received or purified according to "Purification of Laboratory Chemicals". [1] Anhydrous tetrahydrofuran (THF) and diethyl ether (Et2O) were obtained from an Inert PS-MD-6 solvent purification system. All other solvents were dried using standard methods if necessary. [1] Yields refer to isolated yields of compounds estimated to be >95% pure as determined by 1 H-NMR spectroscopy. APCI mass spectra were recorded on an Advion Expression CMS L via ASAP probe or direct inlet. Low Resolution ESI mass spectra were recorded on an Agilent 6120 Series LC/MSD system. Low resolution EI mass spectra were recorded on an Agilent 5977A Series GC/MSD system. High resolution (HR) EI mass spectra were recorded on a double focusing mass spectrometer ThermoQuest MAT 95 XL from Finnigan MAT. HR-ESI and HR-APCI mass spectra were recorded on a Bruker Impact II. All Signals are reported with the quotient from mass to charge m/z. IR spectra were recorded on a Nicolet Thermo iS10 scientific spectrometer with a diamond ATR unit. The absorption bands ̃ are reported in cm −1 .

Borane-mediated Reduction of Carboxylic acids (GP2)
In modification of a reported procedure, [2] the o-iodobenzoic acid derivative (S1, 1.00 equiv) was dissolved in dry THF (1.00 M). After cooling to 0 °C, BH3SMe2 (1.20 equiv) were added dropwise over 15 min. After the addition, the mixture was allowed to warm to rt and stirred for 16 h. After completion of the reaction, the mixture was cooled to 0 °C and MeOH (40 µl/mmol) was carefully added. Afterwards, 1 M Na2CO3 solution (0.5 ml/mmol) was slowly added. The resulting mixture was diluted with water (3 ml/mmol) and extracted with Et2O (3 × 5 ml/mmol). The combined organic phases were washed with brine (5 ml/mmol), dried over Na2SO4 and concentrated under reduced. The crude product was purified by column chromatography on silica gel.

Iodine catalysed Acetylation of Benzylic alcohols (GP3)
In modification of a reported procedure, [3] the o-iodobenzyl alcohol derivative (S2, 1.00 equiv) was suspended in Ac2O (6.00 equiv). If necessary, dichloromethane (0.1-0.2 ml/mmol) was added. Iodine (0.100 equiv) was added and the mixture was stirred at rt. The conversion was monitored via TLC and after full conversion the mixture was diluted with water (0.5 ml/mmol) and sat. NaHCO3 solution (2 ml/mmol). The aqueous phase was extracted with dichloromethane (1 ml/mmol). The combined organic phases were washed with sat. Na2S2O3 solution, dried over Na2SO4 and concentrated under reduced pressure. The crude product was either used as received or purified by column chromatography on silica gel.

Primary Benzyl Acetates
The o-iodobenzoic acid derivative S1a were commercially available and have been used as received for the synthesis of the corresponding alcohols.

2-Iodobenzyl acetate ( 3a)
Following a reported procedure, [1] o-iodobenzoic acid (49.6 g, 200 mmol 1.00 equiv) was dissolved in dry THF (200 ml). After cooling to 0 °C, NaBH4 (21.9 g, 580 mmol, 2.90 equiv) was added portionwise. To the resulting mixture, I2 (38.1 g, 150 mmol, 0.750 equiv) in THF (300 ml) was slowly added over 5 h. After the addition, the mixture was allowed to warm to rt and stirred overnight. After completion of the reaction, the mixture was cooled to 0 °C and water (70 ml) was carefully added. Afterwards, 3 M HCl was slowly added until the solution was at pH 2. The resulting mixture was extracted with Et2O (4 × 150 ml). The combined organic phases were washed with 1 M Na2CO3 (200 ml), sat. Na2S2O3 (50 ml) and brine (200 ml

S13
The reaction was performed in a continuous flow reactor based on three syringe pumps, one reaction chamber (0.10 ml) at room temperature and an electrochemical Flow Reactor (Vapourtec -Ion Electrochemical Flow Reactor, Volume = 0.60 ml, spacer 0.50 mm, 0.10 ml·min −1 ). All parts were joined with T-Pieces as shown in scheme S3. An in flow precooled (for 20 min @ 0 °C) solution of benzyl alcohol 4 (0.4 M, 1.00 equiv) and the corresponding arene (4.0 M, 10.0 equiv) in MeNO2 was mixed with an in flow precooled (for 20 min @ 0 °C) solution of TfOH (0.8 M, 2.00 equiv) in MeNO2 and reacted at 0 °C for 2 min at a combined flowrate of 0.05 ml·min −1 . Afterwards a solution of n-BuN4BF4 (10 mM) in TFE was added to the stream and the flow was subjected to electrolysis by employing a glassy carbon (GC) anode and a platinum cathode. The electrolysis was performed under CCE (j = 2.67 mA·cm −2 , 2 F) at a total combined flowrate of 0.10 ml·min −1 . The first two reactor volumes were discarded to reach a steady state. After collecting for 3 h 20 min the solution was concentrated by reduced pressure and the product was first precipitated and afterwards washed with Et2O to obtain the corresponding iodininium salt.